Opposite regulation of endothelial NO synthase by HSP90 and caveolin in liver and lungs of rats with hepatopulmonary syndrome

Abstract

The hepatopulmonary syndrome is a complication of cirrhosis that associates an overproduction of nitric oxide (NO) in lungs and a NO defect in the liver. Because endothelial NO synthase (eNOS) is regulated by caveolin that decreases and heat shock protein 90 (HSP90) that increases NO production, we hypothesized that an opposite regulation of eNOS by caveolin and HSP90 might explain the opposite NO production in both organs. Cirrhosis was induced by a chronic bile duct ligation (CBDL) performed 15, 30, and 60 days before sample collection and pharmacological tests. eNOS, caveolin, and HSP90 expression were measured in hepatic and lung tissues. Pharmacological tests to assess NO released by shear stress and by acetylcholine were performed in livers (n = 28) and lungs (n = 28) isolated from normal and CBDL rats. In lungs from CBDL rats, indirect evidence of high NO production induced by shear stress was associated with a high binding of HSP90 and a low binding of caveolin to eNOS. Opposite results were observed in livers from CBDL rats. Our study shows an opposite posttranslational regulation of eNOS by HSP90 and caveolin in lungs and liver from rats with CBDL. Such opposite posttranslational regulation of eNOS by regulatory proteins may explain in part the pulmonary overproduction of NO and the hepatic NO defect in rats with hepatopulmonary syndrome.

Possible mechanisms involved in the discrepancy of hepatic and aortic endothelial nitric oxide synthases during the development of cirrhosis in rats

“…A recent study has shown that on the first day after portal vein ligation in rats, early upregulation of eNOS activity is an initial event leading to NO overproduction and vasodilatation (6). Similar opposite regulation of eNOS has been observed in the liver and lungs of cirrhotic rats with the hepatopulmonary syndrome (22). eNOS phosphorylation by Akt was shown to be a potential mechanism for the induction of eNOS activity.…”

EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis

“…The increased release of nitric oxide in the pulmonary circulation is related to an increased expression and activity of two isoforms of nitric oxide synthase (NOS), the endothelial NOS (eNOS) and the inducible NOS (iNOS). [511][512][513][514][515][516] Meanwhile, BT and the BT-related endotoxaemia and pro-inflammatory response also contribute to the accumulation of macrophages in the pulmonary microvasculature. 517 Endothelial activation of fractalkine (CX3CL1), a chemokine, in the lung may favour the adherence of monocytes in the pulmonary microcirculation.…”

Radicicol, a heat shock protein 90 inhibitor, reduces glomerular filtration rate

“…In an elegant study, Frossard et al (9) showed an opposite regulation of eNOS by HSP90 since greater NO synthesis in the lungs was associated with elevated eNOS and HSP90 interaction, whereas the contrary effect was observed in liver homogenates, in which NO production was decreased. Thus lesser NO production in the liver was attributed to eNOS-HSP90 uncoupling together with enhanced association of eNOS to the caveolin.…”